Drug addiction has a detrimental sociological and economic impact upon the U.S. as well as the entire wond. By exacting its toll on families and communities, it not only affects the present, but also future generations. Addiction to the psychomotor stimulant cocaine is characterized by a progressive escalation and loss of control over drug intake despite the negative consequences associated with continued drug use. This process involves long-term neuroadaptations within the circuitry of the brain that is normally dedicated to reward and incentive learning. Our goal is to provide a clearer understanding of the biochemical basis of the effects that cocaine has on behavior. Reward learning, as well as drug seeking behavior is dependent upon both increased glutamatergic and dopaminergic neurotransmission within the striatum. Glutamate activates Ca2+-dependent signaling cascades, while dopamine invokes G-protein coupled cAMP-dependent signaling pathways. The neuronal protein kinase Cdk5 integrates Ca2+ and cAMP signaling and mediates the effects of cocaine. We have found that Cdk5 is constitutively active under basal conditions and provides a negative tonus toward PKA signaling. while activation of NMDA receptors by glutamate in striatal neurons inhibits Cdk5. Thus Cdk5 is uniquely positioned to mediate the biochemIcal effects of cocaine that are necessary for addiction. We propose to study the role of Cdk5 in addiction by characterIzing the effect of conditional loss of Cdk5 on the behavioral responses of mice to cocaine administration, These stud res wilt utilize conditional knockout transgenic technology to delete the Cdk5 gene in adult mice [and will be complemented by the use of novel systemic Cdk5 inhibiting drugs]. The cellular basis for these effects wlR be pursued by characterizing the regulation of Cdk5 via ionotropic glutamate receptors. and the effects of cocaine upon this regulation will be examined in intact brain tissue using a neuropharmacological approach. To specifically define the molecular mechanisms by which Cdk5 mediates cocaine's effects and contributes to addiction, we will characterize novel interactions between Cdk5 and NMDA receptors, which we have discovered contribute to synaptic plasticity that underlies memory formation. By understanding the biology of drug abuse at the biochemical and molecular level, we strive to contribute to the development better treatmems for addiction. (The use of inhibiting drugs will be eliminated.]